The invention relates to a gamma globulin suitable for intravenous administration, which can be obtained from human plasma without modifying processes.
It is known that a gamma globulin can be prepared by fractionation, which has the property of fixing complement non-specifically (Barandun, S., "Die Gamma Globulin-Therapie," S. Karger-Verlag, Basel 1963). This anticomplement activity is related to the formation of aggregates. Non-specific complement fixing gamma globulin is not suitable for intravenous administration, but only for intramuscular use. Since, however, the antibody activity is more complete in intravenous administration, and particularly since it starts immediately, attempts have been made to produce gamma globulin preparations that can be administered intravenously.
It is known that the biological function of antibodies is the elimination of bacteria and viruses and the neutralization of toxins. The antigen-binding part (F.sub.ab) of the antibody molecule provides first for the recognition and neutralization of pathogens. The antigen-antibody complex that forms then activates the complement fixing part (F.sub.c) of the molecule. A series of immunological reactions is thereby initiated, the most important of which are phagocytosis and the specific activation of the complement system. The specific activation of the complement system, which must be clearly distinguished from the non-specific (the anti-complement effect), produces bacteriolysis in the case of bacterial infections. As a further consequence of complement activation, anaphylatoxins and chemotactic factors are "metered" out. The anaphylatoxins, by increasing tissue permeability, provide for an increased antibody concentration at the site of the infection, while the chemotactic factors support phagocytosis. Thus, in the defense against infection, the F.sub.c part of the immunoglobulin-G molecule is of far-reaching importance. Of especial importance clinically is the in vivo half-life of the antibodies contained in intravenous gamma globulin. The longer the in vivo half-life, the longer the antibodies will circulate in the blood and the longer they will be available for prophylactic activity. This is of decisive importance in the case of diseases in whose course the organism is not capable of forming antibodies. In such cases it is necessary to administer the antibodies continually. The less often this is the case, the easier it will be to provide ambulatory treatment, especially.
Methods are already known for the production of an intravenously tolerable preparation from a standard gamma globulin (human) providing non-specific complement fixation. These methods are based on cleaving hydrolytically or enzymatically into its individual fragments the non-specific complement fixing standard globulin (human) obtained by conventional fractionating methods, such as Cohn's alcohol fractionation or Rivanol ammonium sulfate fractionation, and thus eliminating the non-specific complement-fixation or eliminating the anticomplement activity by chemical modification with beta-propiolactone. Specifically, these methods are the following:
Pepsin Decomposition (Schultze, H. E., and Schwick, C.: Dtsch. med. Wochenschrift, 87, 1643 (1962)). PA1 Decomposition (Barandun, S. et al.: Vox Sang. 28, 157 (1975)). PA1 Hcl Treatment (Barandun, S. et al.: Vox Sang. 7, 187 (1962)). PA1 Beta-Propiolactone Treatment (Stephan, W.: Z. klin. Chem. klin. Biochemie 7, 282 (1969)).
With regard to the half-life, the half-life of all known preparations is less than the natural half-life of 18 to 22 days. This is due to the drastic modification of the molecule by the enzymatic decomposition: antibody fragments are formed which have a high elimination rate. Controlled chemical modification by betapropiolactone delivers a decidedly better product having a half-life of 15 days. This, however, does not always achieve the object of the invention, namely, the isolation and concentration of human immune globulins having a natural, unaltered half-life of 18 to 22 days, free of anti-complement activity and therefore suitable for intravenous administration.